SUO 2023: First Results from BOND-003, a Phase 3 Study of Intravesical Cretostimogene Grenadenorepvec Monotherapy for Patients with High-Risk BCG Unresponsive NMIBC

( The 2023 SUO annual meeting included a late breaking abstract session on urothelial cancer, featuring a presentation by Dr. Mark Tyson discussing the first results of BOND-003, a phase 3 study of intravesical Cretostimogene grenadenorepvec monotherapy for patients with high-risk BCG- unresponsive NMIBC.

Cretostimogene Grenadenorepvec is a highly immunogenic conditionally replication adenovirus, and its oncolytic immunotherapy mechanism is that it encodes GM-CSF with insertion of the human EF2-1 promoter:
It binds to the Coxsackie Adenovirus Receptor (CAR) leading to robust expression in all stages of bladder cancer, and subsequent viral replication results in tumor lysis.

Dr. Tyson notes that oncolytic immunotherapy is selective oncolysis and potent antitumor response, with the following steps:

  1. Targeting and destroying cancer cells
  2. Stimulation of anti-tumor response

BOND-003 is a phase 3 trial of cretostimogene monotherapy for BCG-unresponsive high-risk NMIBC with CIS. The trial is a single-arm, open-label, intravesical administration of cretostimogene monotherapy for patients with pathologically confirmed BCG-unresponsive high-risk NMIBC with CIS +/- Ta/T1. Patients had all Ta/T1 disease resected prior to treatment, with mandatory biopsies at the 12-month assessment. The dosing regimen is an induction course of six weekly treatments, with the option for a second induction of six weekly treatments for non-responders. The maintenance course is weekly x 3 every 3 months for year 1 and then weekly x 3 every 6 months for year 2. The endpoints for the trial are complete response at any time, complete response at 12 months, duration of response, progression free survival, and recurrence free survival.

Among 66 patients evaluable (October 5, 2023), the majority of patients are male (76%), white (56%), and older than 65 years of age (80%). ECOG status was primarily 0 (80%), with the majority having previously received TICE BCG (83%). Of note, this was a very heavily pretreated cohort with 14 median number of BCG instillations (range: 7-47). The complete baseline characteristics are as follows:
BOND-003 characteristics
The first results from BOND-003 included a 75.7% (95% CI 63% - 85%) complete response rate at any time based on central review. This in the context of all patients having active disease at baseline prior to enrollment and having received adequate BCG therapy as per FDA 2018 Guidance on BCG-unresponsive NMIBC. Additionally, 74.4% (95% CI 58% - 86%) (32/43) of responders maintained a response for >= 6 months. Full complete response and duration of complete response data is as follows:BOND-003 duration table
Cretostimogene also showed durable response over time with 31% of patients who were not initial responders being salvaged with re-induction. The Swimmer’s plot for this trial is as follows:BOND-003 complete response swimmer plot
Cretostimogene has been generally well tolerated, with most adverse events being grade 1-2, with 2 patients (1.8%) having serious treatment-related adverse events (grade 2). There were no grade >= 3 treatment-related adverse events reported, no treatment discontinuations due to adverse events, and no deaths were reported:BOND-003 trae
Dr. Tyson emphasized that cretostimogene has the potential to disrupt the NMIBC treatment landscape, with a current look at the trials in this disease space:trial landscape table
The next phase of the BOND-003 trial includes two important aspects:

  1. Treatment extension
  • Maintenance extension – complete responders are eligible for maintenance through year 3
  • Maintenance dosing – weekly x 3 every 3 months in year 1, and weekly x 3 every 6 months in year 2 and year 3
  1. Addition of a BCG-unresponsive papillary cohort (n = 70)
  • Dosing schedule: standard cretostimogene induction and maintenance schedule
  • Summary of changes: patients are not eligible for second induction course or maintenance upon recurrence

Additionally, the SUO-CTC Trial, PIVOT-006, is a phase 3 trial of adjuvant cretostimogene versus TURBT alone in intermediate risk NMIBC, with over 90 North American sites participating in the study and the first site already open. Dr. Tyson concluded his presentation discussing the first results of BOND-003 by highlighting that the FDA has granted fast track designation for Cretostimogene monotherapy in BCG-unresponsive CIS with or without Ta/T1 papillary disease.

Presented by: Mark D. Tyson, MD, MPH, Mayo Clinic Arizona, Phoenix, AZ

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023.